Cocaine at doses of 30 mg/kg or more produces on acute hepototoxic effect in mice pretreated for four days with either phenobarbital or 3-methylcholanthrene. Both of these agents act in induce microsomal drug metabolism of the liver. Under a similar protocol no hepatotoxicity was observed in phenobarbital pretreated rats, guinea pigs, or rabbits. Metabolism studies in vivo and in vitro with isolated hepatocytes from mouse and rat indicate that the hepatotoxicity is related to the rate of formation and subsequent metabolism of narcocaine to a toxic metabolite. No covalent binding of radiolabelled material was observed following administration of H3-cocaine to PB-pretreated mice. studies with ethanol and 4-propylpyrazole as inhibitors of alcohol dehydrogenase (ADN) indicate that ADH activity may be involved in metabolism of norcocaine to a toxic metabolite. Hepatotoxicity was not prevented by reserpine, indicating that the toxicity is not related to the catecholamine effect of cocaine.